Although it is well recognized that interferon-± (IFN-±) is involved in the development of systemic inflammatory response syndrome, a condition characterized by loss of endothelial barrier function, whether or not IFN-± has any direct effect on endothelial cell (EC) death is unclear. Furthermore, which signal transduction pathway involved in IFN-±-induced EC apoptosis remains to be elucidated. To answer these questions, we investigated the effect of IFN-± on EC death (apoptosis versus necrosis) and the underlying signal transduction pathway responsible for IFN-±-induced EC apoptosis. IFN-± resulted in a dose-dependent increase in EC apoptosis after 24 h incubation (p < .05). However, IFN-± did not induce EC necrosis. Tumor necrosis factor-± (TNF-±), but not lipopolysaccharide (LPS), had a augmentative effect on IFN-±-induced EC apoptosis (p < .05), while both of them alone failed to induce EC apoptosis. These results indicate that exposure of EC to IFN-± can cause apoptosis rather than necrosis. Both calcium ionophore, A23187, and the protein kinase C (PKC) activator phorbol-myristate-acetate (PMA) had a synergistic effect on IFN-±-induced EC apoptosis (p < .05). However, neither the calcium chelator 1,2–bis 2–aminophenoxy ethane-N,N,N',N'-tetraacetic acid (BAPTA), nor the PKC inhibitor 1 −5–isoquinolinysulfonyl 2–methyl piperazine (H-7) attenuated IFN-±-induced EC apoptosis. Three specific tyrosine protein kinase (TPK) inhibitors, herbimycin A, tyrphostin, and genistein, significantly inhibited IFN-±-induced EC apoptosis in a dose-dependent fashion (p < .05). Furthermore, the activation of TPK in EC by IFN-± was completely abrogated by these TPK inhibitors. These findings suggest that the signal transduction pathway required for induction of EC apoptosis by IFN-± is TPK dependent and is independent of calcium and PKC.
©1999The Shock Society